The centromedian and parafascicular nuclei (CM/PF) of the thalamus receive inputs from the basal ganglia, and send a massive and topographically organized projection back to the striatum. Projections from the CM terminate in the putamen, completing a movement-related trans-thalamic feedback loop by which basal ganglia output may act to shape striatal output under normal and pathologic conditions. The CM/PF complex is increasingly targeted for neurosurgical interventions, such as deep brain stimulation (DBS), in the treatment of conditions such as Tourette syndrome, Parkinson's disease and others. The clinical use of CM/PF-DBS is empiric at this time. In preliminary studies in monkeys, we have found that electrical CM stimulation results in complex sequences of activation and inhibition in striatal cells, which are not easily explained by simple activation of the glutamatergic CM-striatal projection. We hypothesize that the striatal responses to CM stimulation are due to secondary spread of activity through striatal neural elements, such as local inhibitory axon collaterals and cholinergic interneurons which may shape the responses of nearby cells. The proposed primate studies will examine this issue in normal and parkinsonian monkeys, using a combination of electrophysiologic recordings, microdialysis experiments, microinjections, and anatomic studies. We will examine the effects of electrical CM stimulation on striatal neuronal activity (Aim 1) through electrophysiologic recordings, microinjections and microdialysis studies. The anatomy of the CM-projections to striatal output neurons is known in some detail, while much less is known about the CM-projection to the cholinergic interneurons. We plan to carry out a detailed light- and electron-microscopic study of the subsynaptic connectivity of these striatal cells (Aim 2). Previous neuropathology studies in parkinsonian patients and dopamine-depleted rodents have suggested that parkinsonism is associated with neuronal degeneration in CM. Because such changes may substantially alter the effects of stimulation and the impact of CM output on striatal activity, we plan under Aim 3 to examine the role of the CM-striatal system and the effects of CM stimulation in monkeys rendered parkinsonian by injections of the dopaminergic neurotoxin 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), using methods similar to those under Aim 1. The studies under Aim 4, finally, will assess parkinsonism-associated changes in CM cell counts, using stereological methods, and changes in the subsynaptic connectivity of cholinergic neurons, using methods similar to those under Aim 2. The studies proposed here will provide us with information regarding the anatomy and physiology of the thalamostriatal system, and its involvement in parkinsonism, will clarify the effects of electrical stimulation of CM under normal and parkinsonian conditions, and will provide data to help clinicians optimize parameters for CM-DBS therapy. PUBLIC HEALTH RELEVANCE The planned studies will examine the functional relationship between two brain regions that are suspected to be involved in the development of parkinsonism and other disorders, i.e., the centromedian nucleus of the thalamus and the striatum. Electrical stimulation of the thalamus is currently used empirically as a treatment for several of these conditions. The planned electrophysiological and anatomical experiments aim to clarify the functional and anatomical interactions between thalamus and striatum under normal and parkinsonian conditions, and will evaluate the effects of electrical stimulation of the thalamus on striatal activity in order to define the mechanism of therapeutic electrical thalamic stimulation, and to help clinicians to optimize deep brain stimulation therapy.